Andrew Halestrap is Emeritus Professor of Biochemistry and Senior Research Fellow at Bristol University. His research interests include how lactic acid crosses cell membranes and the role of mitochondria in the healthy and diseased heart. He has published more than 200 original research papers, is an elected Fellow of the Academy of Medical Sciences and was awarded Keilin Memorial Lecture of the Biochemical society in 2010. He is Chairman of Christians in Science and has served in various leadership roles in his church and in academia including being a past Chair of both the British Heart Foundation Project Grants Committee and the Bristol Heart Institute.
Describe something that has recently amazed you and how it made you feel.
My scientific career has continually provided new revelations that amaze me and it is difficult to pick just one recent example. However, in the last couple of years I have started working with Baker’s Yeast (Saccharomyces cerevisiae to give it its proper name) and have had to read up about its metabolism (cellular chemistry). The intricacy and complexity of this has amazed me and especially the many unusual products synthesised by yeast that give different wines and beers their distinctive flavours. And it is all going on inside a cell that is not visible to the naked eye and that is almost indestructible!
How would you personally define wonder, awe and curiosity? And how do they relate to each other?
I think of awe and wonder as the emotional responses to something that is amazingly beautiful, intricate or perfectly fitted for its purpose or context. They are “wow” moments that you want to share with others. Curiosity then follows because I want to know how something works or why something happens. This is driven by a desire to understand.
What inspires you to be creative?
I am not sure that I am very creative, but I do like to find solutions to problems, either theoretical or practical. That is critical for scientific research and sometimes requires thinking “outside the box”, perhaps in response to something you experience / learn about in a totally different context. It is often difficult to pin down where ideas come from, and serendipity (unexpected observations) can be important. It is recognising the significance of these events (which sometimes happen because you do something wrong in an experiment!) that can lead to major breakthroughs.
Do you have any ‘rituals’ or an environment that aids your creativity?
Nothing special here, although lying in the bath sometimes really does bring Eureka moments (it did for Archimedes!) and I often get ideas when walking. Relaxation and recreation are vital to maintaining a fresh and fertile mind, and ideas can pop into your head when you least expect them to.
What do you love about magic?
There is a definite sense of wonder and amazement. I know that I am being deceived and that there is a logical explanation for what appears impossible. So I cannot avoid applying my scientific brain to ask how it was done – but I rarely succeed!
What do you think hinders an audience from experiencing wonder when watching a magician?
May be too much showmanship and glamour can distract me from the extraordinary events unfolding before my eyes. But then, is the distraction essential for the trick to work as ones attention is diverted from the sleight of hand demanded by the trick!? In my view the best magicians do not appear to draw attention to themselves (or their assistants).
Where do you think our sense of wonder comes from and what can we do to cultivate it?
At a scientific level I think it is an integral part of the way our brains work. The different sensory inputs that we share with other animals interact with our emotions, enquiring minds and aesthetic sense that are uniquely well developed in the human brain and this induces the experience of wonder. However, for me, as a Christian, it is also part of what it means to be made in the image of God because it helps me look beyond the physical world to see the majesty and power of its creator. I think we can cultivate a sense of wonder by taking time to reflect on and enjoy each experience and share it with others.
As a non-specialist can you tell me about your area of research into heart attacks?
I should say that I have had major research projects in areas of research other than the heart, including studies related to diabetes, cancer and exercise, but the heart has been a major focus of my research for the last 20 years and has probably had the greatest clinical impact. I will try and explain what I have been doing without being too technical.
A human heart consists of millions of cells, and each cell contains hundreds of mitochondria that convert energy from food into chemical energy – ATP (adenosine triphosphate) – in a process that also uses oxygen. Since the heart beats over 100 000 times a day, pumping 7 thousand litres of blood around the body, a healthy population of mitochondria is essential to provide the energy needed for heart contraction. Lack of oxygen supply to the heart can prevent mitochondria producing enough ATP. Such oxygen deprivation occurs when the blood supply becomes impaired or prevented (ischaemia) and this occurs in angina, coronary thrombosis (heart attack), and during cardiac surgery (when the heart is stopped so that surgeons can operate on it). To salvage the heart it is important to restore the flow of blood as quickly as possible (reperfusion), but this process itself can damage the heart. This is because the mitochondria undergo a process that makes them leaky and converts them from being energy providers to cell killers that cause irreversible damage to the heart. We were the first to demonstrate the importance of this Jekyll-to-Hyde transition in mitochondria and have been at the forefront of elucidating its molecular mechanism. This has enabled us to develop drugs and protocols to prevent this transition and minimise damage to the heart.
Where and how did the breakthroughs come about? What motivates you?
There have been many key moments in my research, rather than one or two major breakthroughs. The initial ideas came out of research I was carrying out on how the liver regulates blood sugar levels. Mitochondria play a key role in this process too, and some observations I made during these studies made me look back at some much earlier published work that I thought might shed light on my results. It did (that’s another story!), but it also led me to recognise that under some conditions the mitochondria could become leaky and if that occurred it might cause cells to die. One condition where this seemed very likely to occur was in the ischaemic / reperfused heart and so we set out to investigate whether this occurred. We developed techniques to demonstrate this directly (the idea of how to do this really did come to me in the bath!) and also identified drugs that prevented the mitochondrial damage and showed they protected the heart from damage. In parallel we were investigating the molecular mechanism of the Jekyll-to-Hyde transition and the different triggers that induced it. We have made a number of significant advances in these areas but it would be difficult to point to a single major breakthrough and there are still many unanswered questions and differences of opinions between other researchers in the field.
Motivation? Curiosity is at the heart of the fundamental research I do on mechanisms, but a desire to see clinical benefits on patients with heart disease motivates me to collaborate with clinicians to apply my research to the clinical setting.
Do you see a link between what you’re doing in a lab and what’s happening on an operating table?
Very much so. My research in the laboratory has led to several clinical trials aimed at protecting hearts during heart surgery or treatment for coronary thrombosis. These are still on going and have certainly influenced clinical procedures, but have not yet saved many lives. It remains possible that new and better drugs that protect the mitochondria will be found and have greater clinical impact. Indeed, several research groups and drug companies continue to develop this area of research in the expectation of a positive outcome.
How much of scientific research is based on a hunch, taking a risk or just a jump into the dark?
Scientific research is mainly a progressive journey; a little like opening Russian Dolls you solve one problem or answer one question only to be confronted by another. One of my colleagues, when researching a new area often asks the question “If I were God how would I have done it?”. In other words, what mechanism might explain this? Now let’s devise experiments to see whether that is the case. Serendipity does sometimes play a key role in major breakthroughs. The unexpected result that crops up, sometimes because of a mistake in the way the experiment was performed, may actually provide new insights and avenues to explore. At other times, you may be listening to a talk, or reading a scientific paper, perhaps in a totally different area to your own, and it sparks an idea in your mind that seems to make sense of your own data. There is always an element of risk in that pursuing a new idea may lead nowhere, and without positive results and publications getting the next grant will be more difficult. But “safe” research that doesn’t address difficult problems is unlikely to lead to major breakthroughs. I have always tried to hold a balance in my research between some more routine studies that will yield publishable but not very exciting data and some more adventurous research that may or may not work.
Previously you were the chair of the British Heart Foundation Project Grants Committee, how do you balance been good stewards of money whilst also recognising that a lot of research is speculative?
All grant applications are reviewed by 3 or 4 experts in the field and their reports discussed by a committee of experienced scientists. The key criteria for funding is whether the project is good science, addressing an important question, based on good preliminary data, appropriately designed, properly costed and ethically sound. All research is speculative to some extent in that if you already knew the result you wouldn’t be doing the research! So what we look for is a plausible hypothesis that is based on good preliminary evidence or theoretical considerations and that is experimentally testable. Often the committee reject an initial application but invites a resubmission that includes new preliminary data and answers to questions and criticisms raised. Short-term funding may even be offered to enable pilot experiments to be performed before major funding is granted. Of course, with limited funds available there will be grant applications that are scientifically sound but of insufficient priority to attract funding. And the committee must always balance the risk of a research project not working and the potential benefits if it does. The track record of the applicant will probably have some influence here because you are more likely to take a risk with someone who has consistently produced good data in the past and advanced the field.
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